Dihydrocarbyl hydrocarbyl phosphonates are a group of stable, organic phosphonic acid esters that are known to possess unique properties. These materials are neutral esters of phosphonic acids and tend to be clear, colorless, and mobile liquids. They are similar in many respects to the trihydrocaryl phosphates which have found a wide variety of commercial applications. The significant structural difference between the two is that the phosphonates have one hydrocarbyl radical attached directly to the phosphorous atom by a carbon-phosphorous bond. This structural difference gives the phosphonates several advantages over the phosphates, among these are higher flash points, greater thermal and hydrolytic stabilities, and different solubility characteristics.
Recently, halogenated versions of these phosphonates have been recognized as being extremely valuable intermediates for many commercially desirable products in the agricultural fields; e.g., products used in insecticidal, fungicidal, plant growth regulation, and bactericidal applications; as additives such as plasticizers in the polymer, resin and polymer fields; and ingredients in gasoline, lubrication, and fuel oil additive compositions. Most importantly, these halogenated phosphonates, especially highly purified compositions of these halogenated phosphonic acid diesters have been in great demand as starting materials for the synthesis of medicinal products, e.g., primarily as building blocks for pharmaceutical intermediates, and certain of these compounds have been known to possess remarkable medicinal activity in their own right, for example, as hypoglycemic and/or antiatherogenic agents (U.S. Pat. No. 4,268,507). These compounds provide an important means to introduce phosphonic moiety or moieties into active drugs.
The halogenated hydrocarbyl phosphonate esters to which the present invention is directed can be prepared by a number of synthetic methods known to those skilled in the art; however, the improved process discovery of this invention specifically relates to compounds prepared by the Michaelis-Arbuzov type reaction of phosphites with halogenated materials.
In 1992, Gobel et al. (Phosphorous, Sulfur and Silicon and Related Elements (1992), 73 (1-4), 67-80) while working to obtain diisopropyl bromomethylphosphonate for the synthesis of diphosphonylmethanes with different constituents on both phosphorous atoms via an Arbuzov type reaction scheme, reacted triisopropyl phosphite (0.25 moles) with methylene bromide (aka dibromomethane or DBM) (0.64 moles), i.e., a ratio of phosphite to DBM of 1:2.56 at from 145-150° C. and the reaction afforded yields of 48% diisopropyl bromomethylphosphonate together with 40% undesired tetraisopropyl methylenephosphonate after 47 hours. These results do not appear to be purified yields.
The reaction scheme of this reference is illustrated in (i) and (ii) below:CH2Br2+RO—P(OR)2→—RBr→BrCH2—P(O)(OR)2   (i)BrCH2—P(O)(OR)2+RO—P(OR)2→—RBr→  (ii)(RO)2—P(O)—CH2—P(O)—(OR)2 
In 1995, Ezquerra et al. (Synthetic Communications (1995) 25(2), 191-4) published their activities relating to improving the Arbuzov type reaction yield of diethyl bromomethyl phosphonate also by removing the ethyl bromide by-product as it formed and by increasing the triethyl phosphite to dibromomethane reactant ratio to 1:4.
It was postulated that the primary reaction schemes are as depicted in (iii), (iv), and (v) below:P(OEt)3+CH2Br2→BrCH2—P(O)(OEt)2+EtBr   (iii)BrCH2—P(O)(OEt)2+P(OEt)3→(EtO)2P(O)—CH2—P(O)(OEt)2+EtBr   (iv)EtBr+P(OEt)3→Et—P(O)(OEt)2   (v)
Ezquerra et al.'s approach was to increase the amount of dibromomethane relative to the triethylphosphite and to remove the ethyl bromide as it formed, and, in this manner, the by-product reaction schemes as depicted in (iv) and (v) would be minimized.
The reaction was conducted at about 100° C. for 48 hours while inert gas was gently bubbled through the reaction medium. After distillation of the liquid, diethyl bromomethyl phosphonate was obtained in a 40% yield.
Also illustrative of the present state of the art, in 1998, R. Waschbusch et al. [Laboratoire Heteroelements et Coordination, URA CNRS 1499, DCPH, Ecole Polytechnique, Palaiseau, France, Comptes Rendus de l'Academie des Sciences, Series 11c: Chimie (1998), 1(1), 49-52] published the results of a third study relating to activities seeking high yields and purity of diethyl dibromofluoromethyl phosphonate. In all these studies, a Michaelis-Arbuzov reaction between essentially equimolar quantities of triethyl phosphite and fluorotribromomethane, i.e., a 1:1 molar ratio, was used to form the phosphonate product.
The first study [Burton D. J., Flynn R. M., J. Fluorine Chem. 10 (1977) 329] was conducted at ambient temperatures in a diethyl ether solvent in the presence of light, suggesting a photo-catalyzed, i.e., a radical reaction mechanism; and reportedly resulted in low product yields. A second study [Waschbusch R., Carran J., Savignac P., Tetrahedron 52 (1996) 14199] reproduced the above-described process; failed to achieve acceptable yields; and switched to a hexane environment. This ambient temperature process realized better yields but required unacceptable reaction times of fourteen days.
The Waschbusch et al. group conducted the reaction also starting with a 1:1 molar ratio of the phosphite to the fluorotribromomethane in the presence of hexane. The reaction mixture was placed in a pressure bottle; sealed; and heated to 50° C. for 48 hours.
The reaction scheme is as depicted in (vi) below:P(OEt)3+FCBr3→FBr2—C—P(O)(OEt)2+EtBr   (vi)
The hexane was evaporated on a rotary evaporator and the crude liquid distilled under reduced pressure to give 79-85% of the diethyl 1,1-dibromo-1-fluoromethylphosphonate product. The excellent product yield with low by-product impurities was realized by the Waschbusch et al. process primarily as a result of the reactivity of the fluorine atom. Because the Arbuzov reaction with fluorine is able to be carried out at such relatively low temperatures, the ethylene bromide by-product is unable to react with the phosphite starting material. Furthermore, the diethyl dibromofluoromethyl phosphonate is not as reactive as the starting FCBr3, therefore it does not effectively react with the phosphite at this low temperature to give the diphosphonate by-product.
To date, the art has been unable to utilize Michaelis-Arbuzov reactions to produce high yields with commercially practicable purification means of dihydrocarbyl halohydrocarbyl phosphonates without using the fluorine atom and the attendant low temperature reactions as set forth in Waschbusch et al.
Accordingly, it is an object of this invention to provide a practical and efficient process for forming non-fluoro halohydrocarbyl phosphonic acid diesters in high selectivity and yield using controlled reaction conditions. It is also an object of this invention to provide an improved process for forming non-fluorohalohydrocarbyl phosphonic acid esters having increased purity.
Other objects will be evident from the ensuing description and appended claims.